The long-term objective of the proposed trial, entitled International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), is to define the role of an invasive approach in patients with stable ischemic heart disease (SIHD). The trial hypothesis is that cardiac catheterization followed by complete revascularization plus optimal medical therapy (OMT) is superior to OMT alone as the strategy for initial management of patients with moderate-to-severe ischemia on stress imaging. The primary endpoint will be time to cardiovascular death, myocardial infarction (MI), or hospitalization for an acute cardiac event (unstable angina, resuscitated cardiac arrest, or heart failure). We will also test the hypothesis that the invasive strategy will improve quality of life. Cost effectiveness will be assessed. The COURAGE and BARI-2D trials found that an initial management strategy of coronary revascularization did not reduce the risk of death or MI in SIHD compared with OMT alone when patients were selected based on coronary anatomy. These data have prompted inference that cardiac catheterization (cath) may not be required in stable patients. Cath in such patients usually leads to revascularization. COURAGE and BARI-2D included a broad range of severity of myocardial ischemia on provocative testing;most patients had mild-moderate ischemia. However, observational data suggest that revascularization is associated with a lower likelihood of death and MI in patients with moderate-severe ischemia but not in patients with lesser degrees of ischemia. Only about half of patients with moderate-severe ischemia are referred for cath. It is unknown whether use rates for cath and revascularization are appropriate for optimal patient management in the era of modern medical therapy (high dose statins and antiplatelet therapy). This issue cannot be resolved using available data, because prior clinical trials in SIHD have enrolled patients after cath, at which point there is substantial selection bias for enrollment based on anatomy. Given the potential for extension of life and avoidance of adverse clinical cardiac events as a result of revascularization, and the significant expense and risks associated with invasive management, the role of an invasive strategy is critically important to define. The proposed ISCHEMIA trial will be a prospective, multicenter, international, randomized, controlled trial that will directly address the need for an invasive strategy, cath and revascularization, in patients with SIHD. We plan to enroll approximately 8,000 patients from among 400-500 sites with moderate-severe ischemia and left ventricular ejection fraction >35% who are recruited after stress imaging. Patients who meet eligibility criteria will undergo blinded coronary CT angiography to exclude significant left main coronary artery disease and nonobstructive disease. Patients randomized to the invasive group will undergo optimal revascularization following study guidelines. Project Narrative: This trial will inform clinicians and patients about a very common question they encounter: when a patient has a moderately to severely abnormal cardiac stress test, is it better to do an angiogram (take a picture of the heart arteries) with the intention of opening or bypassing any blockages with stents or surgery plus optimal medical therapy, or is it better to optimize medical therapy and only consider the angiogram if symptoms cannot be controlled? If there is a benefit to invasive testing and treatment, then clinicians and patients must be made aware of these benefits and put them into practice to prevent bad outcomes like heart attacks and death;if the results show there is no benefit from routine invasive testing, then treatment would begin with only intensive lifestyle change and medication to control symptoms and reduce risk. Either finding could provide much-needed information to guide practice and improve quality of medical care. (End of Abstract)